Heat-shock protein 90: A novel autoantigen in human carotid atherosclerosis

Businaro, Rita; Profumo, Elisabetta; Tagliani, Angela; Buttari, Brigitta; Leone, Stefano; d’Amati, Giulia; Ippoliti, Flora; Leopizzi, Martina; D’Arcangelo, Daniela; Capoano, Raffaele; Fumagalli, Laura; Salvati, Bruno; Riganò, Rachele

doi:10.1016/j.atherosclerosis.2009.04.026

Cited by 63 publications

(52 citation statements)

References 46 publications

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“…Both thymic ABs and MVs contained alpha enolase, a glycolytic enzyme that has been recently suggested to play a role in rheumatoid arthritis and other autoimmune diseases [25][26][27]. Furthermore, we detected the presence of heat shock proteins implicated as autoantigens in atherosclerosis [28,29]. Our work has also revealed the presence of histones (H1-H4) in both ABs and MVs.…”

Section: Discussionsupporting

confidence: 65%

Proteomic characterization of thymocyte-derived microvesicles and apoptotic bodies in BALB/c mice

Turiák

Misják

Szabó

et al. 2011

Journal of Proteomics

131

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Section: Discussionsupporting

confidence: 65%

Proteomic characterization of thymocyte-derived microvesicles and apoptotic bodies in BALB/c mice

Turiák

Misják

Szabó

et al. 2011

Journal of Proteomics

131

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“…Indeed, DMAG administration dose-dependently reduced the size and extension of atherosclerotic lesions in STZ-induced diabetic apoE 2/2 mice and also altered plaque composition without any incidence in lipid profile. Increased HSP90 expression has been linked to vulnerability of human advanced atherosclerotic lesions, and therefore it has been suggested as a promising target to stabilize atheroma plaques through the modulation of inflammation and oxidative stress (17,18,40). Our observations in diabetic mice revealed that DMAG treatment promoted a less inflamed, more stable phenotype characterized by lower content of lipids, macrophages, and T cells and higher collagen and VSMC content.…”

Section: Discussionsupporting

confidence: 51%

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

et al. 2015

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Heat shock proteins (HSPs) are induced by cellular stress and function as molecular chaperones that regulate protein folding. Diabetes impairs the function/expression of many HSPs, including HSP70 and HSP90, key regulators of pathological mechanisms involved in diabetes complications. Therefore, we investigated whether pharmacological HSP90 inhibition ameliorates diabetes-associated renal damage and atheroprogression in a mouse model of combined hyperglycemia and hyperlipidemia (streptozotocin-induced diabetic apolipoprotein E-deficient mouse). Treatment of diabetic mice with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG, 2 and 4 mg/kg, 10 weeks) improved renal function, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leukocyte infiltration, and fibrosis), and expression of proinflammatory and profibrotic genes. Furthermore, DMAG significantly reduced atherosclerotic lesions and induced a more stable plaque phenotype, characterized by lower content of lipids, leukocytes, and inflammatory markers, and increased collagen and smooth muscle cell content. Mechanistically, the renoprotective and antiatherosclerotic effects of DMAG are mediated by the induction of protective HSP70 along with inactivation of nuclear factor-kB (NF-kB) and signal transducers and activators of transcription (STAT) and target gene expression, both in diabetic mice and in cultured cells under hyperglycemic and proinflammatory conditions. In conclusion, HSP90 inhibition by DMAG restrains the progression of renal and vascular damage in experimental diabetes, with potential implications for the prevention of diabetes complications.

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“…Documented local self-antigens include heat shock proteins, oxidized LDL, and native lipoproteins (1)(2)(3)(4)(5)(6)(7)(8). Most recently, we have demonstrated autoimmunity to the ␣1(V) chain of col(V) to be a consistent feature of atherosclerosis in human CAD and in the Apoe Ϫ/Ϫ mouse model (17).…”

Section: Discussionmentioning

confidence: 92%

“…It is increasingly accepted that autoimmunity constitutes some portion of the pathological processes underlying atherosclerosis, with oxidized LDLs, native lipoproteins, and heat shock proteins identified as autoantigens involved in atherogenesis (1)(2)(3)(4)(5)(6)(7)(8). Recognition of the autoimmune aspects of atherosclerosis has suggested the possibility of employing immunomodulatory approaches to ameliorate symptoms.…”

mentioning

confidence: 99%

Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

Park¹,

Huang²,

Jankowska‐Gan

et al. 2016

Journal of Biological Chemistry

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We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe ؊/؊ mouse model. We have also shown sensitization of Apoe ؊/؊ mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr ؊/؊ mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the ␣1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr ؊/؊ mice, suggesting future courses of experimentation for the characterization of such epitopes.Atherosclerosis underlies coronary artery disease (CAD) 3 and stroke, major global causes of death (1), and is a chronic inflammatory disease that is modulated by both innate and adaptive immune pathways. It is increasingly accepted that autoimmunity constitutes some portion of the pathological processes underlying atherosclerosis, with oxidized LDLs, native lipoproteins, and heat shock proteins identified as autoantigens involved in atherogenesis (1-8). Recognition of the autoimmune aspects of atherosclerosis has suggested the possibility of employing immunomodulatory approaches to ameliorate symptoms. That such an approach is feasible has been borne out in studies in which blockage of T cells reactive to native lipoprotein ApoB100 (4) or mucosal or subcutaneous immunization with HSP65 (9, 10), oxidized LDL (11), native ␤2-glycoprotein I (12), or apolipoprotein B-100 peptide (13, 14) have been shown to be atheroprotective. Collagens can compose up to 60% of the total protein content in atherosclerotic plaques (15) and stimulate the growth and inflammation of atheromas (16). We have shown previously that interleukin 17-dependent autoimmunity to type V collagen col(V)) is a consistent feature of atherosclerosis in advanced CAD in humans and in Apoe Ϫ/Ϫ mice on a high-fat diet (17). Moreover, the same study provided evidence of a causative role for col(V) autoimmunity in the pathogenesis of atherosclerosis because sensitization of Apoe Ϫ/Ϫ mice on normal chow to col(V) has been shown to markedly increase the ...

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Heat-shock protein 90: A novel autoantigen in human carotid atherosclerosis

Cited by 63 publications

References 46 publications

Proteomic characterization of thymocyte-derived microvesicles and apoptotic bodies in BALB/c mice

Proteomic characterization of thymocyte-derived microvesicles and apoptotic bodies in BALB/c mice

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

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